US6262045B1 - 4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivatives, their preparation and their application in therapy - Google Patents

4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivatives, their preparation and their application in therapy Download PDF

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US6262045B1
US6262045B1 US09/463,634 US46363400A US6262045B1 US 6262045 B1 US6262045 B1 US 6262045B1 US 46363400 A US46363400 A US 46363400A US 6262045 B1 US6262045 B1 US 6262045B1
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mmol
methyl
pyridazino
dihydro
indole
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Yannick Evanno
Laurent Dubois
Mireille Sevrin
Frank Marguet
Jacques Froissant
Régine Bartsch
Catherine Gille
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse

Definitions

  • the subject-matter of the present invention is compounds of general formula (I)
  • X represents a hydrogen or halogen atom or a methyl, methoxy or phenylmethoxy group
  • Y represents a hydrogen atom, 1 or 2 halogen atoms or a hydroxyl, methoxy, nitro or methyl group
  • R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group
  • R 2 and R 3 each represent, independently of one another, a hydrogen atom, a (C 1 -C 4 )alkyl group or a phenylmethyl group,
  • R 2 and R 3 form, with the nitrogen atom which carries them, an azetidinyl, pyrrolidinyl, 3-ethoxypyrrolidinyl, piperidinyl, morpholinyl, 4-methylpiperazinyl or 1,3-thiazolidinyl group, the respective formulae of which are as follows:
  • the preferred compounds are those in the general formula of which X is in the 8 or 9 position and represents a hydrogen or halogen atom, Y represents a hydrogen atom, R 1 represents a methyl or ethyl group, R 2 represents a hydrogen atom or a methyl group and R 3 represents a methyl group or else R 2 and R 3 form, with the nitrogen atom which carries them, an azetidinyl or pyrrolidinyl ring.
  • reaction intermediate is then treated at room temperature with an alcohol of general formula R′′OH, in which R′′ represents a (C 1 -C 4 )alkyl group, in order to obtain the diester of general formula (III), or else the compound of general formula (II) is reacted with an alkyl chloroglyoxylate in a polar aprotic solvent, such as dichloromethane, at room temperature, in the presence of a Lewis acid, for example titanium tetrachloride, in order to obtain the diester of general formula (III).
  • a polar aprotic solvent such as dichloromethane
  • This alcohol (V) is subsequently converted to the halogenated compound of general formula (VIII) by any reaction known to a person skilled in the art, either, for example, treatment with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as dichloromethane, or else by the action of a chlorinating agent, such as methanesulphonyl chloride, in a mixture of solvents, such as tetrahydrofuran and pyridine.
  • a chlorinating agent such as methanesulphonyl chloride
  • a nucleophilic substitution reaction with the cyanide ion is subsequently carried out, either in a mixture of polar solvents, such as dimethylformamide and water, at a temperature of 20 to 80° C., or in a two-phase mixture, such as water and dichloromethane, between room temperature and the reflux temperature, in the presence of a phase transfer agent, in order to obtain the compound of general formula (IX).
  • polar solvents such as dimethylformamide and water
  • An acidic hydrolysis is subsequently carried out, for example by using a mixture of acetic acid and of hydrochloric acid, at the reflux temperature, or else a basic hydrolysis is subsequently carried out, for example by using potassium hydroxide in a mixture of solvents, such as water and 2-methoxyethanol, at the reflux temperature, in order to obtain the compound of general formula (X).
  • This acid is subsequently converted to the secondary or tertiary amide of general formula (I) by reaction with an amine of general formula HNR 2 R 3 , in which R 2 and R 3 are as defined above, via the intermediacy, for example, of the imidazolide obtained by reaction with 1,1′-carbonylbis-1H-imidazole.
  • the compound of general formula (II) as defined above is converted to a compound of general formula (VI) by any method known to a person skilled in the art, for example by an electrophilic reaction in acidic medium.
  • the latter is subsequently treated in acetic acid, first at room temperature and then at the reflux temperature, with a phenylhydrazine optionally substituted by a Y group as defined above.
  • a compound of general formula (VII) is obtained, which is converted to the corresponding halogenated derivative of general formula (VIII) by a radical-type reaction, for example by using N-bromosuccinimide, in a solvent such as carbon tetrachloride, in the presence of an agent such as 2,2′-azobis(2-methylpropionitrile).
  • the compound of general formula (VIII) is subsequently treated as described with respect to Scheme 1.
  • a compound of general formula (I), in which Y represents a methoxy group can be converted to a compound in the formula of which Y represents a hydroxyl group by any known method, for example by the action of boron tribromide, in a chlorinated solvent, such as dichloromethane.
  • the aldehyde (XI) is subsequently converted to a nitrile of general formula (XII) by reaction with (4-methylbenzenesulphonyl)methyl isocyanide (“TosMIC”) in a solvent, such as 1,2-dimethoxyethane, in the presence of a base, such as potassium 1,1-dimethylethoxide.
  • the nitrile (XII) is subsequently converted to an ester of general formula (XIII), in which R′′ represents a lower alkyl group, by the action of an acid, such as hydrogen chloride, in an alcoholic solvent of formula R′′OH.
  • this ester (XIII) is converted to the secondary or tertiary amide of general formula (I) by reaction with an amine of general formula HNR 2 R 3 , in which R 2 and R 3 are as defined above, for example in the presence of a trialkylaluminium derivative, in a solvent such as toluene.
  • the dash “-” forms part of the word and the dash “ 13 ” is only used for the line end break; it is to be omitted in the absence of a break and must not be replaced either by a hyphen or by a space.
  • a suspension of 1 g (2.73 mmol) of 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 0.7 g (4.3 mmol) of 1,1′-carbonylbis-1H-imidazole in 200 ml of tetrahydrofuran is stirred for 3 h at 50° C.
  • the reaction mixture is cooled to 25° C., an excess of liquefied dimethylamine is added and the reaction mixture is stirred for 12 h at room temperature.
  • Example 1.5 The preparation is carried out as in Example 1.5, from 15 g (44 mmol) of 8-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one. After several treatments and purifications by silica gel chromatography, 15 g (37 mmol) of solid are isolated.
  • Example 1.6 The preparation is carried out as in Example 1.6, from 12.5 g (3 mmol) of 1-(bromomethyl)-8-chloro-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one in a mixture of chloroform and water. After purification on a column of silica gel, 10 g (28 mmol) of solid are obtained.
  • Example 3.2 The preparation is carried out as in Example 3.2, from 1 g (3 mmol) of 5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and from excess pyrrolidine. The product is recrystallized from propan-2-ol. 0.5 g (1.3 mmol) of solid is obtained.
  • Example 1.1 The preparation is carried out as in Example 1.1, from 20 g (79 mmol) of methyl 4-bromo-1H-indole-2-carboxylate, from 3.8 g of 60% sodium hydride and from 6 ml of iodomethane. After reaction, the solvent is evaporated under reduced pressure and the residue is taken up in water. The mixture is extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated under reduced pressure. The product is dried under reduced pressure. 20.6 g (77 mmol) of solid are obtained.
  • Example 3.2 The preparation is carried out as in Example 3.2, from 3.1 g (7.5 mmol) of 9-bromo-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid, from 1.4 g of 1,1′-carbonylbis-1H-imidazole and from 0.7 ml of pyrrolidine. After reaction, water is added and the precipitate is collected by filtration and dried under reduced pressure. It is recrystallized from propan-2-ol and washed with ether and pentane. It is dried under reduced pressure. 2.3 g (4.9 mmol) of solid are obtained.
  • Example 3.2 The preparation is carried out as in Example 3.2, from 0.78 g (1.9 mmol) of 9-bromo-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid. The product is recrystallized from propan-2-ol. 0.57 g (1.3 mmol) of solid is obtained.
  • Example 1.7 The preparation is carried out as in Example 1.7, from 3.4 g (10.4 mmol) of 5,8-dimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile. 2 g (5.8 mmol) of product are obtained, which product is used as is in the following stage.
  • Example 3.2 The preparation is carried out as in Example 3.2, from 1 g (2.9 mmol) of 5,8-dimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid. The product is recrystallized from propan-2-ol. 0.5 g (1.3 mmol) of solid is obtained.
  • Example 1.3 The preparation is carried out as in Example 1.3, from 5 g (16.2 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro- ⁇ -oxo-1H-indole-3-acetate and from 9.5 ml of phenylhydrazine in 150 ml of acetic acid. 3.9 g (11 mmol) of solid are isolated, which solid is used as is in the following stage.
  • Example 1.4 The preparation is carried out as in Example 1.4, from 4.1 g (10.4 mmol) of ethyl 8-fluoro-5-(methoxymethyl)-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate. 3.2 g (9 mmol) of solid are isolated, which solid is used as is in the following stage.
  • triphenylphosphine triphenylphosphine are added to a solution of 3.2 g (9 mmol) of 8-fluoro-1-(hydroxymethyl)-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one and of 6.3 g (19 mmol) of tetrabromomethane in 200 ml of dichloromethane.
  • the mixture is stirred for 2 h, 50 ml of cyclohexane are added and the precipitate is collected by filtration and dried under reduced pressure.
  • 2.9 g (7 mmol) of solid are isolated, which solid is used as is in the following stage.
  • Example 1.7 The preparation is carried out as in Example 1.7, from 1.2 g (3.3 mmol) of 8-fluoro-5-(methoxymethyl)-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile. After filtration and drying, 1.1 g (3.2 mmol) of solid are isolated, which solid is used as is in the following stage.
  • Example 1.1 The preparation is carried out as in Example 1.1, from 8.0 g (35.8 mmol) of ethyl 6-chloro-1H-indole-2-carboxylate, from 1.8 g of 60% sodium hydride and from 2.8 ml of iodomethane.
  • Hydrogen chloride is added to a solution of 1.83 g (5.25 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in 250 ml of methanol until the solution is saturated and the reaction mixture is stirred for 4 hours at reflux. The mixture is cooled, the reaction mixture is concentrated under reduced pressure and 25 ml of water and 25 ml of methanol are added to the residue. After stirring, the insoluble product is collected by filtration, washed with water and with diethyl ether, dried and purified by chromatography on a column of silica gel. 1.00 g (2.62 mmol) of compound is isolated in the form of a white solid.
  • Me”, “Et”, “Pr” and “Ph” respectively denote a methyl, ethyl, propyl and phenyl group.
  • azetid “pyrrolid”, “piperid”, “morph”, “piperaz” and “thiazolid” respectively denote an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and 1,3-thiazolidinyl group.
  • the compounds of the invention were subjected to pharmacological tests which demonstrated their advantage as substances having therapeutic activities.
  • the affinity of the compounds for the ⁇ 1 receptors of the cerebellum and ⁇ 2 receptors of the spinal cord was determined according to a variant of the method described by S. Z. Langer and S. Arbilla in Fund. Clin. Pharmacol., 2, 159-170 (1988), with the use of [ 3 H]flumazenil instead of [ 3 H]diazepam as radioligand.
  • the cerebellar or spinal cord tissue is homogenized for 60 s in 120 or 30 volumes, respectively, of ice-cold buffer (50 mM Tris-HC1, pH 7.4, 120 mM NaCl, 5 mM KCl) and then, after dilution to 1/3, the suspension is incubated with [ 3 H]flumazenil (specific activity 78 Ci/mmol, New England Nuclear) at a concentration of 1 nM and with the compounds of the invention at different concentrations, in a final volume of 525 ⁇ l. After 30 minutes of incubation at 0° C., the samples are filtered under reduced pressure on Whatman GF/B® filters and washed immediately with ice-cold buffer.
  • ice-cold buffer 50 mM Tris-HC1, pH 7.4, 120 mM NaCl, 5 mM KCl
  • the specific binding of [-H]flumazenil is determined in the presence of 1 ⁇ M unlabelled diazepam.
  • the data are analysed according to standard methods and the IC 50 concentration, the concentration which inhibits by 50% the binding of [ 3 H]flumazenil, is calculated.
  • the IC 50 values of the most closely related compounds of the invention lie between 5 and 1000 nM for the ⁇ 1 receptors of the cerebellum and between 20 and 1000 nM for the ⁇ 2 receptors of the spinal cord.
  • the anxiolytic activity is evaluated in rats in the drink intake conflict test according to the method described by J. R. Vogel, B. Beer and D. E. Clody in Psychopharmacologia (Berl.), 21, 1-7 (1971).
  • the rat After being deprived of water for 48 h, the rat is placed in a soundproof chamber equipped with a water pipette connected to an anxiometer which delivers a mild electric shock every 20 licks.
  • the number of shocks received is automatically counted over 3 minutes and makes it possible to evaluate the anxiolytic activity of the tested compounds.
  • the results are expressed by the minimum effective dose (MED), the dose which produces a significant increase in the number of shocks received, with respect to the number observed in the control animals.
  • MED minimum effective dose
  • the MED values of the most active compounds lie, in this test, between 0.1 and 10 mg/kg via the intraperitoneal or oral route.
  • the rats are placed individually on the central platform, the muzzle directed towards one of the closed arms, and observed for 4 min using a video camera.
  • the time spent by the animal in the open arms, the number of entries into the closed arms and into the open arms, the number of attempts to enter the open arms, followed by an avoidance response, and the exploration of the edges in the open arms are recorded.
  • the results are expressed for each animal: 1) as percentage of passages into the open arms relative to the total number of entries into the four arms of the apparatus, 2) as percentage of time spent in the open arms relative to the total duration of the test (4 min), 3) as total number of abortive attempts made by the animal, 4) as total number of explorations.
  • the products under study are administered intraperitoneally or orally at increasing doses.
  • the results are expressed by the minimum effective dose (MED) which produces either a significant increase (activity in the open arms) or a significant decrease (attempts) relative to the performance observed in the control animals.
  • MED minimum effective dose
  • the MED values of the most active compounds lie, in this test, between 0.1 and 20 mg/kg via the intraperitoneal or oral route.
  • the sedative or hypnotic activity of the compounds was determined by observing their action on the rat's electrocorticogram, according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and by H. Depoortere and M. Decobert, J. Pharmacol., (Paris), 14, 2, 195-265 (1983).
  • the products under study were administered intraperitoneally at increasing doses.
  • the most active compounds induce sleep patterns at doses ranging from 0.1 to 30 mg/kg.
  • test products are administered to the animals intraperitoneally 30 min before an intravenous injection of 20 mg/kg of pentetrazol. Immediately after the injection, the number of animals exhibiting clonic convulsions is noted over 5 min.
  • AD 50 the dose which protects 50% of the animals, calculated according to the method of J. T. Lichtfield and F. Wilcoxon ( J. Pharm. Exp. Ther. (1949), 96, 99-113) on the basis of 3 or 4 doses each administered to a group of 8 to 10 rats.
  • the AD 50 values of the most active compounds lie between 0.1 and 10 mg/kg via the intraperitoneal or oral route.
  • the intrinsic activity of the compounds is determined by the latency time of onset of convulsions induced by the subcutaneous administration of isoniazid (800 mg/kg) simultaneously with the test compound injected intraperitoneally, according to the protocol described by G. Perrault, E. Morel, D. Sanger and B. Zivkovic in Eur. J. Pharmacol., 156, 189-196 (1988).
  • the results are expressed as the AD 50 , the dose which produces 50% of the maximum effect, relative to the control animals, determined on the basis of 3 or 4 doses each administered to a group of 8 to 10 mice.
  • the AD 50 values of the most active compounds lie, in this test, between 1 and 20 mg/kg via the intraperitoneal route and, depending on the compounds, the maximum effect can be as much as 400%.
  • results of the tests performed on the compounds of the invention show that, in vitro, they displace [ 3 H]flumazenil from its ⁇ 1 specific binding sites in the cerebellum and ⁇ 2 specific binding sites in the spinal cord; they exhibit an affinity for the ⁇ 1 and ⁇ 2 sites situated in the GABA A — ⁇ sites—chlorine channel macromolecular complex.
  • disorders of GABAergic transmission such as anxiety, sleep disorders, epilepsy, spasticity, muscle contractures, cognitive disorders, withdrawal disorders related to alcoholism, tobacco or drugs, and the like.
  • They can also be used for the treatment of Parkinson's disease and all types of extrapyramidal syndromes. Finally, they can be used in premedication and as general anaesthetics for the induction and/or maintenance of anaesthesia, or as local anaesthetics, optionally in combination with other anaesthetics and/or muscle relaxants and/or analgesics.
  • compositions form appropriate for enteral, parenteral or transdermal administration such as tablets, dragees, capsules, including hard gelatin capsules, suspensions or solutions to be swallowed or injected, such as syrups or phials, transdermal patches, and the like, in combination with suitable excipients, containing a dose which permits a daily administration of 1 to 1000 mg of active substance

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US09/463,634 1997-07-30 1998-07-28 4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivatives, their preparation and their application in therapy Expired - Lifetime US6262045B1 (en)

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FR9709692A FR2766823B1 (fr) 1997-07-30 1997-07-30 Derives de 4-oxo-3,5-dihydro-4h-pyridazino[4,5-b] indole-1-acetamide, leur preparation et leur application en therapeutique
FR97/09692 1997-07-30
PCT/FR1998/001667 WO1999006406A1 (fr) 1997-07-30 1998-07-28 DERIVES DE 4-OXO-3,5-DIHYDRO-4H-PYRIDAZINO[4,5-b] INDOLE-1-ACETAMIDE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE

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US20050124615A1 (en) * 2002-04-03 2005-06-09 Jacques Froissant 3-heteroarly-3,5-dihydro-4-oxo-4h-pyridazino[4,5-b] indole-1-acetamide derivatives, preparation and use thereof in medicaments
WO2007027525A1 (en) 2005-08-29 2007-03-08 Sanofi-Aventis U.S. Llc Novel crystalline form of a pyridazino [4 , 5-b] indole derivative
US20080038359A1 (en) * 2005-05-05 2008-02-14 Sanofi-Aventis U.S. Llc Stable Nanoparticle Formulations
US20080095343A1 (en) * 2006-10-20 2008-04-24 Huawei Technologies Co., Ltd. Method, system and co switch for implementing bills association
US20080160080A1 (en) * 2005-08-29 2008-07-03 Sanofi-Aventis U.S. Llc Amorphous solid dispersions
US20110224214A1 (en) * 2008-08-18 2011-09-15 Sanofi-Aventis U.S. Llc Process for preparing polymorph

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US7235554B2 (en) 2002-04-03 2007-06-26 Sanofi-Aventis 3-heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5-b] indole-1-acetamide derivatives, preparation and use thereof in medicaments
US20070219202A1 (en) * 2002-04-03 2007-09-20 Sanofi-Aventis 3-Heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5 b]indole-1-acetamide derivatives, their preparation and their application in therapeutics
US7323467B2 (en) 2002-04-03 2008-01-29 Sanofi-Aventis 3-heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5-b]indole-1-acetamide derivatives, their preparation and their application in therapeutics
US20080076775A1 (en) * 2002-04-03 2008-03-27 Sanofi-Aventis 3-Heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5-b]indole-1-acetamide derivatives, their preparation and their application in therapeutics
US7405306B2 (en) 2002-04-03 2008-07-29 Sanofi-Aventis 3-Heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5-b]indole-1-acetamide derivatives, their preparation and their application in therapeutics
US20080038359A1 (en) * 2005-05-05 2008-02-14 Sanofi-Aventis U.S. Llc Stable Nanoparticle Formulations
US20080139569A1 (en) * 2005-08-29 2008-06-12 Sanofi-Aventis U.S. Llc. Novel crystalline form
US20080160080A1 (en) * 2005-08-29 2008-07-03 Sanofi-Aventis U.S. Llc Amorphous solid dispersions
WO2007027525A1 (en) 2005-08-29 2007-03-08 Sanofi-Aventis U.S. Llc Novel crystalline form of a pyridazino [4 , 5-b] indole derivative
US7683062B2 (en) * 2005-08-29 2010-03-23 Sanofi-Aventis U.S. Llc Crystalline form
US7713548B2 (en) 2005-08-29 2010-05-11 Sanofi-Aventis U.S. Llc Amorphous solid dispersions
EA014164B1 (ru) * 2005-08-29 2010-10-29 САНОФИ-АВЕНТИС Ю.Эс. ЭлЭлСи Новая кристаллическая форма производного пиридазино[4,5-в]индола
AU2006285142B2 (en) * 2005-08-29 2012-06-14 Sanofi-Aventis U.S. Llc Novel crystalline form of a pyridazino [4 , 5-b] indole derivative
US20080095343A1 (en) * 2006-10-20 2008-04-24 Huawei Technologies Co., Ltd. Method, system and co switch for implementing bills association
US20110224214A1 (en) * 2008-08-18 2011-09-15 Sanofi-Aventis U.S. Llc Process for preparing polymorph

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ATE226584T1 (de) 2002-11-15
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FR2766823A1 (fr) 1999-02-05
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AU8983298A (en) 1999-02-22
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